Albert W. Garofalo
Thermo Fisher Scientific
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Featured researches published by Albert W. Garofalo.
Bioconjugate Chemistry | 2014
Penelope M. Drake; Aaron E. Albers; Jeanne Baker; Stefanie Bañas; Robyn M. Barfield; Abhijit Bhat; Gregory W. de Hart; Albert W. Garofalo; Patrick G. Holder; Lesley C. Jones; Romas Kudirka; Jesse M. McFarland; Wes Zmolek; David Rabuka
It is becoming increasingly clear that site-specific conjugation offers significant advantages over conventional conjugation chemistries used to make antibody–drug conjugates (ADCs). Site-specific payload placement allows for control over both the drug-to-antibody ratio (DAR) and the conjugation site, both of which play an important role in governing the pharmacokinetics (PK), disposition, and efficacy of the ADC. In addition to the DAR and site of conjugation, linker composition also plays an important role in the properties of an ADC. We have previously reported a novel site-specific conjugation platform comprising linker payloads designed to selectively react with site-specifically engineered aldehyde tags on an antibody backbone. This chemistry results in a stable C–C bond between the antibody and the cytotoxin payload, providing a uniquely stable connection with respect to the other linker chemistries used to generate ADCs. The flexibility and versatility of the aldehyde tag conjugation platform has enabled us to undertake a systematic evaluation of the impact of conjugation site and linker composition on ADC properties. Here, we describe the production and characterization of a panel of ADCs bearing the aldehyde tag at different locations on an IgG1 backbone conjugated using Hydrazino-iso-Pictet-Spengler (HIPS) chemistry. We demonstrate that in a panel of ADCs with aldehyde tags at different locations, the site of conjugation has a dramatic impact on in vivo efficacy and pharmacokinetic behavior in rodents; this advantage translates to an improved safety profile in rats as compared to a conventional lysine conjugate.
Bioorganic & Medicinal Chemistry Letters | 2009
Anh P. Truong; Danielle L. Aubele; Gary D. Probst; Martin L. Neitzel; Chris M. Semko; Simeon Bowers; Darren B. Dressen; Roy K. Hom; Andrei W. Konradi; Hing L. Sham; Albert W. Garofalo; Pamela S. Keim; Jing Wu; Michael S. Dappen; Karina Wong; Erich Goldbach; Kevin P. Quinn; John-Michael Sauer; Elizabeth F. Brigham; William Wallace; Lan Nguyen; Susanna S. Hemphill; Michael P. Bova; Guriqbal S. Basi
In this Letter, we report our strategy to design potent and metabolically stable gamma-secretase inhibitors that are efficacious in reducing the cortical Abetax-40 levels in FVB mice via a single PO dose.
Bioorganic & Medicinal Chemistry Letters | 2013
Albert W. Garofalo; Marc Adler; Danielle L. Aubele; Simeon Bowers; Maurizio Franzini; Erich Goldbach; Colin Lorentzen; R. Jeffrey Neitz; Gary D. Probst; Kevin P. Quinn; Pam Santiago; Hing L. Sham; Danny Tam; Anh P. Truong; Xiaocong M. Ye; Zhao Ren
Leucine rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinsons disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of cinnoline-3-carboxamides that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays. These compounds are also shown to be potent inhibitors in a cellular assay and to have good to excellent CNS penetration.
Journal of Medicinal Chemistry | 2013
Gary Probst; Danielle L. Aubele; Simeon Bowers; Darren B. Dressen; Albert W. Garofalo; Roy K. Hom; Andrei W. Konradi; Jennifer Marugg; Matthew N. Mattson; Martin L. Neitzel; Chris M. Semko; Hing L. Sham; Jenifer Smith; Minghua Sun; Anh P. Truong; Xiaocong M. Ye; Ying-zi Xu; Michael S. Dappen; Jacek Jagodzinski; Pamela S. Keim; Brian T. Peterson; Lee H. Latimer; David A. Quincy; Jing Wu; Erich Goldbach; Daniel Ness; Kevin Quinn; John-Michael Sauer; Karina Wong; Hongbin Zhang
Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aβ generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aβ in the CSF of healthy human volunteers.
Bioorganic & Medicinal Chemistry Letters | 2013
Albert W. Garofalo; Marc Adler; Danielle L. Aubele; Elizabeth F. Brigham; David Chian; Maurizio Franzini; Erich Goldbach; Grace Kwong; Ruth Motter; Gary D. Probst; Kevin P. Quinn; Lany Ruslim; Hing L. Sham; Danny Tam; Pearl Tanaka; Anh P. Truong; Xiaocong M. Ye; Zhao Ren
Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinsons disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD. Herein we report our findings on a series of 4-alkylamino-7-aryl-3-cyanoquinolines that exhibit kinase inhibitory activity against both wild type and G2019S mutant LRRK2. Activity was determined in both biochemical and cellular assays. Compound 14 was further evaluated in an in vivo pharmacodynamic study and found to significantly inhibit Ser935 phosphorylation after oral dosing.
Bioorganic & Medicinal Chemistry Letters | 2013
Maurizio Franzini; Xiaocong M. Ye; Marc Adler; Danielle L. Aubele; Albert W. Garofalo; Shawn Gauby; Erich Goldbach; Gary D. Probst; Kevin P. Quinn; Pam Santiago; Hing L. Sham; Danny Tam; Anh P. Truong; Zhao Ren
Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinsons disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of [1,2,4]triazolo[4,3-b]pyridazines that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays and show an unprecedented selectivity towards the G2019S mutant. A structural rational for the observed selectivity is proposed.
Bioorganic & Medicinal Chemistry Letters | 2010
Matthew N. Mattson; Martin L. Neitzel; David A. Quincy; Christopher M. Semko; Albert W. Garofalo; Pamela S. Keim; Andrei W. Konradi; Michael A. Pleiss; Hing L. Sham; Elizabeth F. Brigham; Erich Goldbach; Hongbin Zhang; John-Michael Sauer; Guriqbal S. Basi
Utilizing a pharmacophore hypothesis, previously described gamma-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide-pyrazoles, with high in vitro potency, good brain penetration, low metabolic stability, and high clearance.
Bioorganic & Medicinal Chemistry Letters | 2010
Xiaocong M. Ye; Andrei W. Konradi; Jenifer L. Smith; Danielle L. Aubele; Albert W. Garofalo; Jennifer Marugg; Marty Neitzel; Chris M. Semko; Hing L. Sham; Minghua Sun; Anh P. Truong; Jing Wu; Hongbin Zhang; Erich Goldbach; John-Michael Sauer; Elizabeth F. Brigham; Michael P. Bova; Guriqbal S. Basi
Significant improvement in metabolic stability on the pyrazolopiperidine scaffold over the original series were achieved and this stability improvement translated in an improved in vivo efficacy.
Bioorganic & Medicinal Chemistry Letters | 2011
Danielle L. Aubele; Anh P. Truong; Darren B. Dressen; Gary D. Probst; Simeon Bowers; Matthew N. Mattson; Chris M. Semko; Minghua Sun; Albert W. Garofalo; Andrei W. Konradi; Hing L. Sham; Wes Zmolek; Karina Wong; Erich Goldbach; Kevin P. Quinn; John-Michael Sauer; Elizabeth F. Brigham; William Wallace; Lan Nguyen; Michael P. Bova; Susanna S. Hemphill; Guriqbal S. Basi
The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate β-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted.
Bioorganic & Medicinal Chemistry Letters | 2009
Simeon Bowers; Gary D. Probst; Anh P. Truong; Roy K. Hom; Andrei W. Konradi; Hing L. Sham; Albert W. Garofalo; Karina Wong; Erich Goldbach; Kevin P. Quinn; John-Michael Sauer; William Wallace; Lan Nguyen; Susanna S. Hemphill; Michael P. Bova; Guriqbal S. Basi
The structural modification of a series of [3.3.1] bicyclic sulfonamide based gamma-secretase inhibitors is described. Appropriate substitution on the bicyclic scaffold provides a significant increase in the metabolic stability of the compounds resulting in an improved in vivo metabolic profile.